Search

Since the description in 2015 of the MRGPRX2 receptor on mast cells, responsible for pseudo-allergies, our knowledge of this type of allergy-like drug reaction is growing, as has the list of drugs -supposed to be able to induce this type of reaction. Unlike IgE--mediated reactions, these pseudoallergic reactions do not require a prior sensitization, are dose-dependent and predictable, and could be prevented, if the offending drug has to be re-administered, -simply with a reduced rate of perfusion or dose. Genetic factors seem to play a role in the predisposition to this type of reactions, but we do not yet have clinically available tools to diagnose them. This literature review summarizes the discoveries of the last 4 years in this field that seem to challenge many dogmas in allergology.Depuis la description en 2015 du récepteur MRGPRX2 sur les mastocytes, responsable des pseudo-allergies, nos connaissances concernant ce type de réaction médicamenteuse ressemblant à une allergie ne cessent d’augmenter, tout comme la liste de ­médicaments qui pourraient induire ce type de réaction. Con­trairement aux réactions IgE-médiées, les réactions pseudo-­allergiques sont dose-dépendantes et prévisibles, et pourraient être prévenues, en cas de nouvelle administration du médi­cament incriminé, simplement par réduction de la dose ou de la vitesse d’administration. Malheureusement, nous ne disposons pas encore d’outils en clinique permettant de les diagnostiquer. Cette revue de la littérature résume les découvertes des quatre dernières années, qui remettent beaucoup de dogmes en ­question.

Therapeutic antibodies have been successfully developed in neurology. However, their efficacy needs to overcome a main hurdle that is their limited access to the brain. Moreover, the multifactorial characteristics of many neurological diseases complicate the identification of a specific target. In this review, we present the neuroroprotective effect of some monoclonal antibodies and we summarize how they can interact with neurodegenerative and inflammatory processes. Monoclonal antibodies, such as natalizumab, that represent a major achievement in multiple sclerosis, have been approved in this indication and used in the routine practice. Also, they are still in a phase of development in degenerative diseases and mainly aim to counteract the aggregation of misfolded proteins such as amyloid beta or tau proteins. Another strategy in development of new monoclonal antibodies is to block physiological inhibitors of axonal growth and myelination such as Nogo-A or its co-transporter LINGO-1. Finally, the recent approbation by the FDA of monoclonal antibodies against CGRP for migraine treatment has been a major breakthrough that expanded the potential fields of application of antibodies in neurology. Thus, a lot of research efforts are now devoted to improve the galenic forms, the routes of administration and to extend these various approaches to other targets.Les anticorps monoclonaux en neurologie.L’utilisation des anticorps thérapeutiques commence à se développer avec succès en neurologie. Leur efficacité est conditionnée par la capacité à contourner la principale limite à l’utilisation de ces molécules dans ce type d’indication qu’est l’accessibilité au cerveau. Le caractère multifactoriel de ces pathologies neurologiques rend également complexe l’identification d’une cible spécifique. Nous exposons dans cette revue les effets neuroprotecteurs des anticorps monoclonaux et résumons leurs activités sur les mécanismes neurodégénératifs et inflammatoires. Les anticorps monoclonaux, tels que le natalizumab, représentent une avancée importante dans le traitement de la sclérose en plaque (SEP) et sont désormais utilisés en routine. Ce type de thérapeutique est toujours en développement dans les maladies neurodégénératives, en agissant principalement sur l’agrégation des protéines mal repliées, telles que la protéine béta-amyloïde et la protéine tau. Une autre stratégie en développement consiste à bloquer les inhibiteurs physiologiques de croissance axonale et de myélinisation, tels que Nogo-A et son co-transporteur LINGO-1. L’autorisation récente par la food and drug administration américaine des anticorps monoclonaux anti-calcitonin gene-related peptide (CGRP) dans la migraine a soulevé un regain d’intérêt pour ces thérapeutiques en neurologie. La recherche est de ce fait très active pour améliorer les formes galéniques et les voies d’administration et pour étendre ces thérapeutiques à d’autres cibles.

New genetic techniques have made it possible to better understand the implications of the PRRT2 gene (proline rich transmembrane protein 2) in various neurological disorders. Mutations within this gene are responsible for kinesigenic paroxysmal dyskinesias (PKD) as well as for benign familial infantile epilepsy (BFIE), a disease associating infantile convulsions and choreoathetosis (ICCA), a form of familial hemiplegic migraine (FHM type 4), paroxysmal benign torticollis of childhood, and episodic ataxia. We describe the case of an infant, carrying a mutation of the PRRT2 gene, with a classical presentation. Through her progression over time, we raise the question of systematic use of anti-epileptic drugs.

Pulmonary arterial hypertension (PAH) is a disorder in which mechanical obstruction of the pulmonary vascular bed is largely responsible for the rise in mean pulmonary arterial pressure (mPAP), resulting in a progressive functional decline despite current available therapeutic options. There are multiple mechanisms predisposing to and/or promoting the aberrant pulmonary vascular remodeling in PAH, and these involve not only altered crosstalk between cells within the vascular wall but also sustained inflammation and dysimmunity, cell accumulation in the vascular wall and excessive activation of some growth factor-stimulated signaling pathways, in addition to the interaction of systemic hormones, local growth factors, cytokines, and transcription factors. Heterozygous germline mutations in the bone morphogenetic protein receptor, type-2 (BMPR2) gene, a gene encoding a receptor for the transforming growth factor (TGF)-β superfamily, can predispose to the disease. Although the spectrum of therapeutic options for PAH has expanded in the last 20 years, available therapies remain essentially palliative. Over the past decade, however, a better understanding of key regulators of this irreversible remodeling of the pulmonary vasculature has been obtained. New and more effective approaches are likely to emerge. The present article profiles the innovative research into novel pathways and therapeutic targets that may lead to the development of targeted agents in PAH.

The comorbidity of depression and cocaine addiction suggests shared mechanisms and anatomical pathways. Specifically, the limbic structures, such as the nucleus accumbens (NAc), play a crucial role in both disorders. P11 (S100A10) is a promising target for manipulating depression and addiction in mice. We summarized the recent genetic and viral strategies used to determine how the titration of p11 levels within the NAc affects hedonic behavior and cocaine reward learning in mice. In particular, p11 in the ChAT+ cells or DRD1+ MSN of the NAc, controls depressive-like behavior or cocaine reward, respectively. Treatments to counter maladaptation of p11 levels in the NAc could provide novel therapeutic opportunities for depression and cocaine addiction in humans.

Huntington's disease is a rare neurodegenerative disease caused by a pathologic CAG expansion in the exon 1 of the huntingtin (HTT) gene. Aggregation and abnormal function of the mutant HTT (mHTT) cause motor, cognitive and psychiatric symptoms in patients, which lead to death in 15-20 years. Currently, there is no treatment for HD. Experimental approaches based on drug, cell or gene therapy are developed and reach progressively to the clinic. Among them, mHTT silencing using small non-coding nucleic acids display important physiopathological benefit in HD experimental models.

The primary cilium is a specialized organelle, present at the surface of most eukaryotic cells, whose main function is to detect, integrate and transmit intra- and extra-cellular signals. Its dysfunction usually results in a group of severe clinical manifestations nowadays termed ciliopathies. The latter can be of syndromic nature with multi-organ dysfunctions and can also be associated with a morbid obese phenotype, like it is the case in the iconic ciliopathy, the Bardet Biedl syndrome (BBS). This review will discuss the contribution of the unique context offered by the emblematic BBS for understanding the mechanisms leading to obesity via the involvement of the primary cilium together with identification of novel molecular players and signaling pathways it has helped to highlight. In the current context of translational medicine and system biology, this article will also discuss the potential benefits and challenges posed by these techniques via multi-level approaches to better dissect the underlying mechanisms leading to the complex condition of obesity.

The role of primary cilia in adult neurons remains elusive, however their developmental functions during brain morphogenesis have been recently highlighted thanks to mouse models. Unmistakably, they are needed for Hedgehog (Hh)-dependent patterning in the forebrain. Not only for Hh reception itself, but most importantly for a downstream event in the Hh transduction pathway, independent of Hh ligand: the Gli3 processing. Indeed, phenotypes due to cilia disruption in the developing brain, such as early patterning, olfactory bulb or corpus callosum formation, can be rescued by reintroducing Gli3-R (the short truncated form of Gli3 working as a transcriptional repressor of Hh target gene). In addition, primary cilia control the proliferation rate in different neural progenitors in the cortex, the hippocampus and the cerebellum; they are required for proper migration of interneurons. And cilia dysfunction is correlated with hydrocephaly, synaptogenesis defects and aberrant axonal tract projections. Most of these neurodevelopmental defects can be related to the various neurological features frequently observed across the ciliopathy spectrum. And thus, understanding the underlying mechanisms of these diverse functions of primary cilia in the brain is a new fundamental challenge.

Since our seminal study in 2003, much has been written about core planar cell polarity (core PCP) signaling and the inner ear. In just a few years, and using the inner ear as a model system, our understanding of the molecular basis of this signaling pathway and how it can influence the development of tissues in mammals has increased considerably. Recently, a number of studies using various animal models of development have uncovered original relationships between the cilia and PCP, and the study of the hair cells of the inner ear has helped elucidating one of these links. In this review, we highlight the differences of PCP signaling between mammals and invertebrates. In the light of recent results, we sum up our current knowledge about PCP signaling in the mammalian cochlear epithelium and we discuss the impact of recent data in the field. We focus our attention on the interrelationship between asymmetric polarity complexes and the position of the cilium, which is essential for the establishment of the overall tissue polarity.

In a landmark paper published in 1977, G. Albrecht-Buehler described a primary cilium on the surface of migrating fibroblasts, and noticed that cilia are oriented parallel to the direction of migration of fibroblasts. While the presence of a primary cilium on neural progenitors and on post-mitotic neurons was noted long ago, it has been observed on migrating cortical interneurons only recently. As in fibroblasts, the cilium of interneurons controls the directionality of migration. It plays an important role in the reorientation of cortical interneurons towards the cortical plate. The morphogen Shh, which is expressed in the migratory pathway of interneurons, is one of the signals that control this reorientation.

Paraneoplastic cerebellar degeneration may be a manifestation indicative of lung, gynecological or breast cancer. Nevertheless, breast cancer is rarely revealed by the occurrence of a paraneoplastic syndrome.We report a 38-year-old patient who presented a paraneoplastic cerebellar degeneration with anti-Yo antibodies as the presenting manifestation of a breast cancer.The diagnosis of a paraneoplastic neurological syndrome (PNS) should lead to urgent and comprehensive screening for cancer oriented by the type of PNS and the nature of the anti-neuronal antibody.

Neurotrophins are a family of trophic factors well known for their effects on neuronal survival, growth and neuronal differentiation. During the last decade, a large literature has shown in humans and in animal models that nerve growth factor (NGF) is a peripheral mediator of pain, especially in the states of inflammatory pain. NGF synthesis is indeed increased in a wide variety of inflammatory diseases and NGF neutralizing molecules are effective analgesic agents in these models of persistent pain. Therapeutical strategies targeting the sequestering of NGF did yield very encouraging results in clinical trials (stages II and III) but have been on hold since 2010 due to potential harmful effects in combination with non-steroid anti-inflammatory drug. NGF regulates the expression of a second neurotrophin, Brain Derived Neurotrophic Factor (BDNF), in nociceptors. BDNF is released where nociceptors are activated, and it acts as a modulator of pain in the central nervous system and is involved in central sensitization.

The discovery of new drug targets represents a real opportunity for developing fresh strategies against pain. Ion channels are interesting targets because they are directly involved in the detection and the transmission of noxious stimuli by sensory fibres of the peripheral nervous system and by neurons of the spinal cord. Acid-Sensing Ion Channels (ASICs) have emerged as important players in the pain pathway. They are neuronal, voltage-independent depolarizing sodium channels activated by extracellular protons. The ASIC family comprises several subunits that need to associate into homo- or hetero-trimers to form a functional channel. The ASIC1 and ASIC3 isoforms are particularly important in sensory neurons, whereas ASIC1a, alone or in association with ASIC2, is essential in the central nervous system. The potent analgesic effects associated with their inhibition in animals (which can be comparable to those of morphine) and data suggesting a role in human pain illustrate the therapeutic potential of these channels.

Active sensation requires the convergence of external stimuli with representations of body movements. We used mouse behavior, electrophysiology and optogenetics to dissect the temporal interactions among whisker movement, neural activity and sensation of touch. We photostimulated layer 4 activity in single barrels in a closed loop with whisking. Mimicking touch-related neural activity caused illusory perception of an object at a particular location, but scrambling the timing of the spikes over one whisking cycle (tens of milliseconds) did not abolish the illusion, indicating that knowledge of instantaneous whisker position is unnecessary for discriminating object locations. The illusions were induced only during bouts of directed whisking, when mice expected touch, and in the relevant barrel. Reducing activity biased behavior, consistent with a spike count code for object detection at a particular location. Our results show that mice integrate coding of touch with movement over timescales of a whisking bout to produce perception of active touch.

Sphingosine 1-phosphate (S1P) mediates critical physiological responses by its binding to G protein-coupled receptor (GPCR) subtypes, known as S1P receptors. Five distinct mammalian S1P receptors, designated S1P1-5 have been identified, each with a different cellular pattern of expression which influences the responses to S1P. In this review, we briefly outline our understanding of the modes of action and the roles of S1P receptors in the regulation of physiological and pathological functions in the cardiovascular, immune and central nervous system.

Pathological diagnosis plays a major role in the therapeutic management of adult diffuse gliomas. It is based on the histopathological analysis of a representative specimen. Therefore pathologists might be aware of the neuroradiological features of the lesions. Pathologists play a major role in the management of biological resources. Pathologists should classify adult gliomas according to WHO 2007 classification (histological subtype and grade). In addition, in order to provide the histomolecular classification of adult gliomas, search for molecular markers of diagnostic, prognostic or predictive of therapeutic responses must be performed by appropriate and validated immunohistochemical and molecular techniques. In all diffuse gliomas, whatever their grade, search for IDH1 R132H and P53 expression is required. Search for IDH1 minor mutations and IDH2 mutations is required in grade II and III IDH1 R132H negative gliomas whereas 1p19q codeletion should be searched for in grade II and III gliomas with an oligodendroglial component. Search for EGFR amplification and MGMT promoter methylation is recommended. It is strongly recommended to fill the standardized form for pathology and molecular features (validated by the French Society of Neuropathology) in all adult diffuse gliomas.

Changes in the substantia nigra of patients with Parkinson's disease were suspected by Brissaud in the late 19th century. They were subsequently confirmed by Tretiakoff but neglected by Lewy, who described the inclusion bodies that bear his name. The experimental Parkinsonian syndrome caused by reserpine led Carlsson to discover the neuromediatory role of dopamine, a finding at the origin of L-DOPA therapy. Identification of a mutation of the alpha-synuclein gene in cases of familial Parkinson's disease with autosomal dominant transmission was followed by the detection of the protein product in Lewy bodies and neurites. Alpha-synuclein is now recognized as being the main constituent of Lewy bodies. Alpha-synuclein immunohistochemistry has revealed that lesions can extend from the autonomous nervous system to the cortex (in Lewy body dementia). The Lewy body itself does not appear to be the direct cause of symptoms, which correlate better with neuronal death. Neuronal death could be due to metabolic disturbances related to alpha-synuclein accumulation, ubiquitin-proteasome system dysfunction, or oxidative stress. Non-autonomous cell death, caused by neuro-inflammation or gliosis, has also been incriminated.

PACAP et VIP sont deux peptides structuralement reliés qui appartiennent à la classe de neuropeptides comprenant la sécrétine, le glucagon et le growth hormone releasing factor. VIP et PACAP ont de nombreuses fonctions biologiques au niveau du système nerveux et sont considérés comme des agents neurotransmetteurs, sécrétagogues, neuroprotecteurs, neurotrophiques, mitogéniques et comme agents différenciant. VIP et PACAP utilisés à des concentrations de l’ordre du nano-molaire sont décrits comme agents anti-inflammatoires. Dans cette thèse, nous montrons que les neuropeptides PACAP et VIP utilisés à des doses élevées de l’ordre du μ-molaire agissent également comme des molécules pro-inflammatoires au niveau des monocytes humains.Nous montrons aussi qu’au sein des monocytes humains, le PACAP agit par l’intermédiaire du récepteur VPAC-1. Les voies de signalisation activées incluent de façon proximale la PLC et la PI3-kinase et de façon plus distale les voies ERK et p38 des MAP-Kinases et les voies dépendantes de focal adhésion kinase associées à la protéine du cytosquelette paxilline. PACAP induit également un pic calcique résultant d’une mobilisation intra- et extracellulaire de calcium.Au niveau fonctionnel, nous montrons quelle PACAP augmente la production de radicaux libres et l’expression membranaire de l’intégrine CD11b impliquée dans l’adhésion et dans la régulation de nombreuses voies métaboliques.Nous montrons également que de faibles doses de PACAP de l’ordre du nM sont suffisantes pour désensibiliser les monocytes à des concentrations plus importantes de PACAP, concentrations connues pour avoir un effet pro-inflammatoire. Le PACAP a ainsi un double rôle, anti-inflammatoire à faible dose et pro-inflammatoire à dose plus élevé.Nous avons de plus investigué la présence d’une transactivation au niveau des cellules monocytaires. Dans ces cellules, PACAP comme rapporté dans les cellules neuronales, utilise la signalisation NGF/TrkA. PACAP augmente la fraction phosphorée du récepteur TrkA. L’utilisation d’inhibiteur spécifique du récepteur au NGF est associée à une diminution de la phosphorylation des voies PACAP-dépendantes telles que AKT et ERK. L’inhibiteur du récepteur au NGF diminue également la mobilisation calcique induite par le PACAP avec au niveau fonctionnel une diminution de la production de radicaux libres et de l’expression de l’intégrine CD11b. Enfin, l’observation que les voies métaboliques (ERK) et que les fonctions (production de radicaux libres) induites par le NGF au sein des cellules monocytaires est sensible à la pertussis toxine, agent modulant des récepteurs à protéines G, indique que les phénomènes de transactivation entre les voies PACAP/VPAC-1 et NGF/TrkA se font de façon bidirectionnelle.Nous montrons enfin que ;à la fois PACAP et VIP sont des ligands du récepteur proinflammatoire FPRL1 au sein des monocytes induisant l’activation des voies AKT/ERK et la mobilisation calcique, responsables de l’augmentation d’expression de l’intégrine CD11b.Nous montrons cependant qu’il existe une voie propre au récepteur VPAC-1, indépendante de FPRL1, médiée par l’axe cAMP/PKA/p38 responsable spécifiquement d’une activité proinflammatoire avec sécrétion de MMP9 et augmentation membranaire de CD35., Doctorat en Sciences, info:eu-repo/semantics/nonPublished

Intracellular protein filaments intermediate in size between actin filaments and microtubules are composed of a variety of tissue specific proteins. The sequence conservation of the coiled-coil alpha-helical structure responsible for polymerization into individual 10 nm filaments defines a large gene family. Intermediate filaments (IFs) include the nuclear lamins, which are universal in Metazoans, and the cytoplasmic intermediate filaments, which are more varied and form cell type specific networks in animal cells. IFs all share a common tripartite structure consisting of a highly conserved central helical rod domain and variable N-head and C-tail domains. In contrast to actin and tubulin, IFs do not require nucleoside triphosphates such as ATP or GTP for polymerization but they self assemble. According to sequences, the IFs proteins are grouped into seven classes, including five cytoplasmic, one nuclear and one sub-cortical localizations. The search for functions of IFs has led to discoveries of roles in the skin, heart, muscle, liver and brain, in premature aging and of involvement in several degenerative disorders. Mutations in IFs cause or predispose to more than 80 human tissue-specific diseases. Mouse models and gene invalidation have been extremely helpful in eliciting IF role in physiopathology. Besides mechanical role in cell plasticity and stress absorbers, IF functions are related to the capacity to interact with signaling molecules and cell kinases, controlling gene regulatory networks. The reviews herein include a historical perspective about IFs, describe how mutations affect IF structure and assembly properties in desminopathies, inclusion formation in the neurodegenerative Alexander disease, and how they induce multiple disorders in laminopathies.

The impact of autoimmunity on malaria-infection evolution reported by various works has led us to compare reactive patterns of self-dependent systemic IgG from 54 patients aged less than 15 years old to those from 46 subjects older than 15 years. These subjects were divided into 34 Plasmodium falciparum asymptomatic carriers (ACs), 30 cases of uncomplicated malaria (UM), and 36 patients suffering from cerebral malaria (CM) living in the same endemic area. The reactivity of the plasma antibodies against human brain tissue extract was assessed by western blotting. Comparative analysis of reactive bands (linear discriminant analysis, LDA) revealed the existence of patterns that distinguish, among the more susceptible subjects aged less than 15 years old, the different clinical forms. In contrast, in less susceptible subjects aged more than 15 years old, the patterns are homogenous and do not allow the separation of these clinical forms. This self-reactive repertoire might be witnessed as an imprint of the clinical tolerance acquired during the years of living in endemic areas. The singularity of this profile under the age of 15 years might have a prognostic value.

Mental retardation (MR) occurs in 2 to 3 % of the general population and is still not therapeutically addressed. Milder forms of MR result from deficient synaptogenesis and/or impaired synaptic plasticity during childhood. These alterations would result from disequilibrium in signalling pathways regulating the balance between long term potentiation (LTP) and long term depression (LTD) in certain neurons such as hippocampus neurons. To provide mentally retarded children with increased cognitive abilities, novel experimental approaches are currently being developed to characterize signalling status associated with MR and to identify therapeutic targets that would restore lost equilibrium. Several studies also highlighted the major role played by molecular switches like kinases, phosphatases, small G proteins and their regulators in the coordination and integration of signalling pathways associated with synaptic plasticity. These proteins may therefore constitute promising therapeutic targets for a number of cognitive deficiencies.

Paraneoplastic neurological syndrome associated with anti-CV2/CRMP5 antibodies are rare. Various clinical manifestations can occur, cerebellar ataxia, polyneuropathy, optic neuritis with NORB or uveitis. Small cell lung carcinoma is generally responsible.We report the case of a 64-year-old man who developed visual symptoms with papilledema, cerebellar signs, polyneuropathy confirmed with a neurophysiological studies. Anti-CV2/CRMP5 antibodies were present. A small cell lung carcinoma was responsible for this paraneoplastic syndrome revealing the cancer. The paraneoplastic syndrome improved with radio chemotherapy of the cancer alone.A paraneoplastic neurological syndrome must be evoked in case of an atypic neurological syndrome. This diagnostic can be confirmed by the presence of anti-neuronal antibodies. In this case, a small cells cancer of the lung must be research.

Hypogonadotropic hypogonadism (HH) is defined by the absence of sex steroid synthesis associated with the lack of appropriate gonadotrophin secretion. This leads to a variable degree of impuberism, often diagnosed during childhood or adolescence. Genetics of HH involve many genes. However, molecular defects have been identified in only 30 % of patients. Kallmann syndrome (KS) is defined by the association of HH and anosmia. Six genes are involved in KS (KAL1, FGFR1, FGF8, PROK2, PROKR2 and CHD7). However, genetics of KS is complex, because of the variability of the phenotype for a similar molecular defect. Otherwise, heterozygous anomalies are frequently described. Identification in the same patient of several mutations in some of these genes (digenism) could account for this variability. Autosomal recessive transmission is frequently observed in familial cases of HH without anosmia. Molecular alterations have been identified for several neuropeptides or their corresponding receptors, which are involved in the physiology of the gonadotropic axis : GNRHR, KISS1R/GPR54, neurokinin B (TAC3), TACR3 and GNRH1 (and PROK2, PROKR2 and CHD7). Anomalies of leptin or its receptor are also involved in HH cases. A new negative regulating element has been recently identified in humans : RFRP3, which is ortholog of the avian GnIH (gonadotrophin inhibitory hormone). Recent progress about these neuropeptides leads to a new model of comprehension of the gonadotropic axis physiology, from a linear model to a network model, which regulates the central element of regulation of the gonadotropic axis, represented by the GnRH neurons.

Neurodegenerative diseases are more and more prevalent in our aging societies. There is strong evidence that glycogen synthase kinase (GSK)-3b plays a crucial role in Alzheimer's disease (AD). Indeed, it is involved in the regulation of the two major neuropathological hallmarks present in the brains of AD patients. Interestingly, the kinase has been implicated in multiple cellular processes and linked with the pathogenesis and neuronal loss in several neurodegenerative diseases, including Parkinson's and Huntington's diseases, in which abnormally elevated levels of GSK-3b activity have been reported. In this review, we will provide an overview of the current data pointing out the convergent role of GSK-3b in the neuropathological pathways of these diseases. We will also discuss the rationale for the development of specific inhibitors with therapeutic potentials for such devastating human diseases.

Despite the fact that the neurotransmitter dopamine was discovered more than 50 years ago, we still have limited knowledge of its physiological and pathological roles. Recent work has unveiled novel and surprising properties of dopamine neurons and of other key players involved in regulating the dopamine system. For example, the integration of the dopamine signal by its receptors depends on many proteins of diverse signaling pathways and also of other types of receptors that interact with and regulate dopamine receptors: many new promising interactions have been reported during the past few years. Also, we are beginning to discover that chronic treatment with dopamine receptor ligands or other molecules affecting dopaminergic pathways induce long-term molecular, structural and functional rearrangements that could ultimately force us to revisit the mechanism of action of established therapeutic agents. Finally, the discovery of glutamate co-release by dopamine neurons is leading us to reconsider some keys aspects of dopamine neuron physiology.

Polyglutamine expansion diseases are adult-onset inherited neurodegenerative disorders that lead to death 10 to 20 years after the first symptoms. Currently, there is no therapy to fight against these diseases. They include Huntington's disease, spinobulbar muscular atrophy, dentatorubral-pallido-luysian atrophy and six types of spino-cerebellar ataxia. The diseases are caused by a unique mutational mechanism: an expansion of the CAG trinucleotide in the corresponding genes coding for an expanded tract of glutamine in the mutated proteins. Polyglutamine expansion confers to the mutant proteins toxic properties that cause neuronal cell death in brain regions specific to each disease. Thanks to cellular and animal models (fly, fish, mouse and rat) of these diseases, we have considerably improved our understanding of the toxic nature of polyglutamine expansion and the physiopathology, and we are now in position to design and test therapeutic strategies to prevent or delay the disease process.

Thoracic endometriosis (TE) is rare with positive histological diagnosis sometimes difficult, particularly in atypical form. The aim of this study was to identify features which can increase performance of the histolological TE diagnosis and more particularly immuno-histochemical (IHC) contribution with hormonal receptors, smooth muscle actin, Ber-Ep4, CD10 and calretinin antibodies. To address this issue, we retrieved, retrospectively, a large series of 591 pneumothorax operated. Among them, 135 (23%) were females including eight (6%) cases related to TE. Those eight women were surgically treated with resection of pleura (n=6/8), lung (n=5/8) and diaphragmatic samples (n=6/8). Typical histological lesions of endometriosis were observed in six cases among eight. All diaphragmatic samples presented, macroscopically, holes responsible of thoraco-abdominal communication (n=6/6). Endometrial glands and/or endometrial stroma cells were found in the diaphragm (n=5/6) and in the pleura (n=2/6) but were never encountered in the lung (n=0/5). IHC study can confirm the five diaphragmatic localizations and can identify a new localization with expression of hormonal receptors, CD10 and smooth muscle actin in an island of fusiform cells. In conclusion, our study shows 1) the high frequency of diaphragmatic endometriosis localization which holes existence also can explain the pathogenesis, 2) the value of diaphragmatic samples in positive histological diagnosis of TE, 3) IHC interest to confirm endometriosis, particularly in atypical form and to differentiate from mesothelial cells inclusion.

Post-translational protein modifications play essential roles in many aspects of cellular functions and therefore in the maintenance of cell integrity. These protein modifications are involved at all stages of neuronal communication within the central nervous system. Sumoylation is a reversible post-translational protein modification that consists in the covalent labelling of a small protein called SUMO to lysine residues of selected target proteins. Sumoylation is a well characterized regulator of nuclear functions and has recently emerged as a key factor for numerous extranuclear processes. Furthermore, sumoylation has recently been shown to modulate synaptic transmission and is also implicated in a wide range of neurodegenerative diseases.

Autism spectrum disorders (ASD) affect at least 1/200 individuals. They are characterized by impaired communication skills and social interaction, as well as restricted, repetitive and stereotyped behaviours. Recent studies point to a role of a synaptic pathway, including synaptic cell adhesion molecules (neuroligins and neurexins) and scaffolding proteins (SHANK3). Abnormal synapse formation/maintenance and an imbalance between GABAergic and glutamatergic synaptic currents seem to be involved in the etiology of ASD.

Several bacteria of the Clostridium genus (C. botulinum) produce 150 kDa di-chainal protein toxins referred as botulinum neurotoxins or BoNTs. They associate with non-toxic companion proteins and form a complex termed botulinum toxin. BoNTs specifically inhibit vesicular neurotransmitter release. The cellular action of BoNTs can be depicted according to a multi-step model : The toxin's heavy chain mediates binding to specific receptors comprised of a ganglioside moiety and a vesicular protein (SV2 for BoNT type A, synaptotagmin for BoNT type B), followed by endocytotic internalisation of the BoNT/receptor complex. Vesicle recycling induces BoNT internalisation. Upon acidification of vesicles, the light chain of the neurotoxin is translocated into the cytosol. Here, this zinc-endopeptidase cleaves one or two among three synaptic proteins (VAMP-synapto-brevin, SNAP25, and syntaxin). As the three protein targets of BoNT play major role in fusion of synaptic vesicles at the release sites, their cleavage is followed by blockade of neurotransmitter exocytosis. Importantly, as the BoNT receptors and intracellular targets are present in all nerve terminals, the BoNTs are not specific for cholinergic transmission. Duration of their inhibitory action is mainly determined by the the life-time of the toxin's light chain in the cytosol. Sprouting of new nerve-endings, which are retracted when the poisoned nerve terminals have recovered full functionality, may lead to anticipated recovery of the poisoned nerve terminals.

Limbic encephalitis is an inflammatory disease localized to the "grand lobe limbique" defined by Broca in 1878, sometimes restricted to the hippocampus, but sometimes including extralimbic abnormalities. The main features are subacute onset, short-term memory disorders and cognitive impairment, temporal seizures, and hippocampic changes on MRI. A list of underlying causes has recently been published Infectious causes used to be frequent (mainly herpes simplex virus). Paraneoplastic limbic encephalitis is characterized by the presence of various onconeural antibodies, such as AntiHu and ANNA3 (bronchial small cell carcinoma), AntiMa2 (testicular tumor), AntiCV2 (lymphoma, thymoma,...). No such antibodies are detected in 40% of patients. The prognosis of these forms is poor. Voltage-gated potassium channel-associated limbic encephalopathies are due to antibodies targeting potassium channels. Mutations of the genes encoding the Kv11 and Kv12 subunits are responsible for several Shaker syndromes, including neuromyotonia, Morvan's disease, type I episodic ataxia, and limbic encephalitis with hyponatremia. Plasma exchanges and immunotherapy are effective. In patients without detectable antibodies, hippocampic anti-neuropil antibodies should be sought, particularly those targeting N-methyl-D-aspartate receptors. Ovarian teratoma is the usual cause of this type of encephalitis. Surgery and immunotherapy are effective. These disorders have been categorized into those associated with antibodies targeting intracellular antigens (poor-prognosis paraneoplastic encephalitis) and those associated with antibodies targeting antigens reacting with cellular membranes (potassium channelopathies and antineuropil antibodies), which respond to immunotherapy and carry a better prognosis. Limbic encephalitis can also reveal Hodgkin's disease, as in a case observed by the authors.

Periodic paralyses are neuromuscular disorders characterized by attacks of muscle weakness coinciding with changes in blood potassium levels. They are thus classified as hypokalaemic, normokalaemic or hyperkalaemic. Most forms are genetic, with autosomal dominant inheritance. These diseases are channelopathies, i.e. caused by mutations in ion channel genes. The culprit genes encode muscle sodium, calcium and potassium channels. Mutations in calcium or potassium channels cause periodic paralyses of the same type (hypokalaemic periodic paralysis or Andersen-Tawil Syndrome). In contrast, distinct mutations in the gene encoding the sodium channel can cause the entire range of periodic paralysis (hypokalaemic, normokalaemic or hyperkalaemic). The physiological consequences of mutations have been studied with patch-clamp techniques and electromyography. Generally speaking, mutations alter the excitability cycle of the muscle membrane, resulting in a loss of function (paralysis). Electromyographic studies have demonstrated a good correlation between symptoms and physiological parameters, giving rise to a classification that can help orient the molecular diagnosis. Work on the genetics and pathophysiology of periodic paralyses has helped to improve the diagnosis and management of these syndromes.

Using a mouse model relevant for humans, lifespan can be prolonged by reducing IGF-I signaling selectively in the central nervous system. This effect occurred through changes in specific neuroendocrine pathways. Investigating the pathophysiological mechanism, we found that IGF receptors in the brain steered the development of the somatotropic axis, which in turn altered the individual growth trajectory and lifespan. Our work is experimental proof that chronically low IGF-I and low growth hormone (GH) levels favor long lifespan and postpone age-related mortality. Our results, together with other recent reports, challenge the notion that GH can slow down or prevent human aging. This is important because growth hormone is sometimes proposed to elderly people as a substitutive treatment in order to compensate the negative effects of aging.

Autophagy is a cellular mechanism for degrading proteins and organelles. It was first described as a physiological process essential for maintaining homeostasis and cell survival, but understanding its role in conditions of stress has been complicated by the recognition of a new type of cell death ("type 2") characterized by deleterious autophagic activity. This paradox is important in the central nervous system where the activation of autophagy seems to be protective in certain neurodegenerative diseases but deleterious in cerebral ischemia. The development of new therapeutic strategies based on the manipulation of autophagy will need to take into account these opposing roles of autophagy.

Pemphigoid gestationis (PG) is a rare autoimmune bullous dermatosis associated with pregnancy. Its previous designation, herpes gestationis, is obsolete. PG is characterized by a subepidermic separation induced by the presence of peripheral blood autoantibodies against two hemidesmosomal antigens: BPAG1 and BPAG2. Clinical diagnosis is confirmed by histology and positive cutaneous immunofluorescence tests. The most discriminant examination for other pruritic dermatoses of pregnancy is the enzyme-linked immunosorbent assay (Elisa) NC16A BP 180. First-line treatment is local corticosteroid therapy; if local treatment fails, general corticosteroid therapy should be administered. The prognosis is good for mother and child, except that there is a risk of preterm delivery and of moderate fetal growth restriction. Management in a specialized setting is therefore necessary. Recurrence is possible during subsequent pregnancies.

In contrast to monoaminergic (MA-ergic) neurons possessing the whole set of the enzymes for MA synthesis from the precursor amino-acid, some, mostly peptidergic, neurons co-express only one of the enzymes of monoamine synthesis. They are widely distributed in the brain, being particularly numerous in ontogenesis and, in adulthood, under certain physiological conditions. Most monoenzymatic neurons possess one of the enzymes for dopamine (DA) synthesis, tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). TH and AADC are enzymatically active in a substantial number of monoenzymatic neurons, where they are capable of converting L-tyrosine to L-3,4-dihydroxy-phenylalanine (L-DOPA) and L-DOPA to dopamine (DA) (or 5-hydroxy-tryptophan, 5-HTP to serotonin), respectively. According to our data L-DOPA synthesized in monoenzymatic TH-neurons is released and taken up by monoenzymatic AADC-neurons for DA synthesis. Moreover, L-DOPA captured by dopaminergic neurons and serotoninergic neurons serves to stimulate dopamine synthesis in the former and to start DA synthesis in the latter. Cooperative synthesis of MAs is considered as a compensatory reaction under a failure of MA-ergic neurons, e.g. in neurodegenerative diseases like hyperprolactinemia and Parkinson's disease, which are developed primarily because of degeneration of DA-ergic neurons of the tuberoinfundibular system and the nigrostriatal system, respectively. Noteworthy, the neurotoxin-induced increase of prolactin secretion returns with time to a normal level due to the stimulation of DA synthesis by the tuberoinfundibular most probably monoenzymatic neurons. The same compensatory mechanism is supposed to be used under the failure of the nigrostriatal DA-ergic system that is manifested by an increased number of monoenzymatic neurons in the striatum of animals with neurotoxin-induced parkinsonism and in humans with Parkinson's disease. Expression of the enzymes of MA synthesis in non-monoaminergic neurons is controlled by intercellular signals such as classical neurotransmitters (catecholamines), etc. Thus, a substantial number of brain neurons express partly the monoaminergic phenotype, namely individual complementary enzymes of MA synthesis, serving to produce MAs in cooperation, which is considered as a compensatory reaction under the failure of MA-ergic neurons.

The GABA(B) receptors belong to the family of class C metabotropic receptors. They are inhibitory receptors forming obligatory heterodimers. Their analgesic role in the dorsal horn of the spinal cord is well established since more than 25 years ago. However, Baclofen, the reference agonist of the GABA(B) receptor, proved to have little efficiency in clinics in neuropathic patients. It seems therefore useful to decipher GABA(B) functions in the nociceptive circuitry, and their regulation in conditions of chronic pain. In the present review, we will focus first on the distribution of the GABA(B) subtypes. Then, we will consider their pre- and post-synaptic functions in the dorsal horn of naïve rats. Finally, we will document the mechanisms that may lead to receptor impairment in neuropathic conditions.

International audience; In contrast to other vertebrates, in which the adult brain shows limited adult neurogenesis, teleost fish exhibit an unparalleled capacity to generate new neurons as adults, suggesting that their brains present a highly permissive environment for the maintenance and proliferation of adult progenitors. Here, we examine the hypothesis that one of the factors permitting establishment of this favourable environment is estradiol. Indeed, recent data showed that radial glial cells strongly expressed one of two aromatase duplicated genes. Aromatase is the estrogen-synthesizing enzyme and this observation is of great interest, given that radial glial cells are progenitor cells capable of generating new neurons. Given the well documented roles of estrogens on cell fate, and notably on cell proliferation, these data suggest that estradiol could be involved in maintaining and/or activating these progenitors. Examination of recent data in birds and mammals suggests that the situation in fish could well be an exaggeration of a more general mechanism implicating estrogens in neurogenesis. Indeed, there is accumulating evidence that estrogens are involved in embryonic, adult or reparative neurogenesis in other vertebrates, notably in mammals. Contrairement à celui des Vertébrés qui possède une capacité de neurogenèse limitée au cours de la vie adulte, le cerveau des Poissons Téléostéens est connu pour sa capacité à proliférer tout au long de la vie et ce dans l'ensemble des territoires cérébraux. Nous examinons ici l'hypothèse selon laquelle l'un des facteurs qui pourraient participer au maintien et à la prolifération de progéniteurs neuronaux serait être l'oestradiol. En effet, des résultats récents ont établi que les cellules gliales radiaires, qui persistent dans le cerveau de poisson adulte, expriment fortement le gène cyp19a1b, dont le produit est la cytochrome P450 aromatase, enzyme de synthèse des oestrogènes. Compte tenu des rôles bien connus de l'oestradiol sur la prolifération cellulaire, cette observation est particulièrement intéressante car les cellules gliales radiaires sont des cellules progénitrices capables de générer des neurones. Des données récentes obtenues chez les mammifères et les oiseaux suggèrent que dans de nombreuses situations de neurogenèse embryonnaire, adulte ou réparatrice, il existe un lien entre production d'oestrogènes dans les cellules gliales radiaires ou les astrocytes et l'activité proliférative des ces cellules. Il est donc possible que la situation existant chez les poissons adultes corresponde à l'exploitation d'un mécanisme général impliquant les oestrogènes dans la neurogénèse, à des fins de croissance continue du cerveau.

In recent decades our knowledge of the molecular mechanisms of biological clocks has grown expontentially. This has helped to guide the choice of genes studied to explain inter-individual variations seen in circadian rhythms. In recent years analysis of circadian rhythms has advanced considerably into the study of pathological circadian rhythms in human beings. These findings, combined with those obtained from studying mice whose circadian genes have been rendered incapable, have revealed the role of genetic factors in circadian rhythms. This literature review presents an overview of these findings. Beyond our understanding of the functioning of these biological clocks, this knowledge will be extremely useful to analyse genetic factors involved in morbid conditions involving circadian rhythm abnormalities.

International audience; The vertebrate neuron axon has long been considered as devoid of the protein synthesis machinery. During the early nineties however, the cytochemical visualization of identified mRNAs within certain rodent neuron axons challenged this dogma of cellular neurobiology. The aim of this paper is to illustrate, taking mainly the mouse olfactory system as an example, conceptual and methodological approaches developed in particular in my group, that aim at identifying the function of these axonal mRNAs. L'axone des neurones de vertébrés a longtemps été considéré comme étant dépourvu de la machinerie de biosynthèse des protéines. Au début des années 1990 cependant, la visualisation cytochimique d'ARNm dans certains axones de rongeurs est venue bousculer ce dogme de la neurobiologie cellulaire. Le but de cet article est d'illustrer, essentiellement sur l'exemple des neurones sensoriels olfactifs de la souris, les développements conceptuels et méthodologiques développés notamment dans mon équipe, qui visent à identifier les fonctions de ces ARNm axonaux.

Paraneoplastic movement disorders are rare. Reported cases frequently describe association with anti-CV2/CRMP5 antibodies.We report a case of an 80-year-old man who developed sensorial neuronopathy, following by movement disorders mimicking chorea and obsessive-compulsive and behavioral disorders. These manifestations were first considered to be associated with a prostatic adenocarcinoma but PET and surgical biopsy revealed a mediastinal small cell lung carcinoma classically associated with anti-CV2/CRMP5 antibodies.This case demonstrates that in a context of paraneoplastic neurological syndrome, search for a classically associated cancer is necessary in order to institute adapted treatment early, even if another tumor is obvious.

International audience; Amyotrophic lateral sclerosis (ALS) is the most frequent adult onset motor neuron disorder. A subset of ALS cases is linked to mutations in the copper/zinc superoxide dismutase (sod1) gene and detailed phenotypic analysis of transgenic mice overexpressing mutant forms of SOD1 (mSOD1) allowed a better understanding of the pathophysiological mechanisms leading to motor neuron death. The promising results obtained in these animal models however poorly translated into conclusive clinical trials. In this review, we summarize the main pathological mechanisms at work in mSOD1 mice. In particular, recent results showed that the key pathological event was the destruction of the neuromuscular junction rather than motor neuron death. Neuromuscular junction dismantlement is likely the result of a chronic energy deficiency at the level of the whole organism. These results, along with a comparative analysis between the phenotype of mSOD1 mice and ALS patients, suggest new therapeutic strategies and show the interests but also the limits of the animal models. double dagger.